LETTER

REPLY TO BREWER: Liver-targeted ALDH2 inhibition may reduce LETTER alcohol-seeking behaviors with limited side effects Adrien Guillota,1, George F. Koobb, and Bin Gaoa,2

We are pleased to read the Letter from Dr. Brewer (1) such as liver toxicity, neuropathies, and other adverse on our paper in PNAS (2). In our manuscript, we only effects (7–9). In addition, although disulfiram has been briefly discuss our current knowledge about aldehyde repurposed as an anticancer agent (10), chronic disul- dehydrogenase 2 (ALDH2) inhibition therapy for firam treatment may cause elevation of systemic and the treatment of alcohol user disorder (AUD) due to local acetaldehyde levels in alcoholics, thereby in- space limitation. We greatly appreciate Dr. Brewer for creasing the risk of cancer development. elaborating on previousfindingsintheareaof By using liver-specific Aldh2 knockout mice and ALDH2 inhibition therapies that were tested both in in vivo hepatocyte-Aldh2 expression knockdown, we patients and in animal models (1). It is true that the demonstrated that a liver-targeted approach might be effects of ALDH2 genotype on alcohol-seeking behav- sufficient to reduce alcohol-seeking behavior while ior have been well documented (3) and many drugs having limited effects on other metabolic parameters that inhibit ALDH2 activities have been developed to and global body functions (2). Major benefits from treat AUD (4). For example, cyanamide (in the form of such strategies include limiting side effects on other calcium carbimide citrate salt) can inhibit ALDH activ- organs, and cancer due to toxic acetaldehyde buildup ity via its active metabolite and is still used therapeu- in the general blood circulation and in other organs. tically as an alcohol-aversive agent (Temposil) in Finally, such an approach may favor patients’ compli- Europe, Canada, and Japan (4). Disulfiram and cyan- ance to treatment by limiting the unpleasant effects of amide both are potent ALDH inhibitors and thus act as increased circulating acetaldehyde levels. Because alcohol-drinking deterrents, through unpleasant expe- numerous approaches could be used to specifically riences (e.g., nausea, tachycardia, flushing) produced deliver a therapeutic agent to the liver and to the he- by the accumulation of acetaldehyde in the blood of patocytes, such as modified liposomes, apolipopro- treated patients (4). Cyanamide is a second-line drug teins, polymers, or viral vectors (11), it is feasible to compared to disulfiram because of its capacity to pro- specifically inhibit ALDH2 in the liver, and we hope duce greater liver damage compared with disulfiram our study may serve as a basis for the development (4). As described by Dr. Brewer, adjustments of the of liver-targeted AUD treatment. disulfiram therapy have shown promising results and supervised disulfiram treatment currently remains Acknowledgments the most effective therapy in this drug class (5, 6); This work was supported by the intramural program of National however, disulfiram therapy may generate side effects Institute on Alcohol Abuse and Alcoholism, NIH (to B.G.).

1 C. Brewer, Partial ALDH inhibition to facilitate controlled drinking rather than abstinence has already been tried and it works. Proc. Natl. Acad. Sci. U.S.A. 117, 7572 (2020). 2 A. Guillot et al., Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking. Proc. Natl. Acad. Sci. U.S.A. 116, 25974–25981 (2019). 3 H. J. Edenberg, J. N. McClintick, Alcohol dehydrogenases, aldehyde dehydrogenases, and alcohol use disorders: A critical review. Alcohol. Clin. Exp. Res. 42, 2281–2297 (2018). 4 V. Koppaka et al., Aldehyde dehydrogenase inhibitors: A comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol. Rev. 64, 520–539 (2012).

aLaboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892; and bNational Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224 Author contributions: A.G., G.F.K., and B.G. wrote the paper. The authors declare no competing interest. Published under the PNAS license. 1Department of Hepatology/Gastroenterology, Charit ´eUniversity Medical Center, 13353 Berlin, Germany. 2To whom correspondence may be addressed. Email: [email protected]. First published March 3, 2020.

www.pnas.org/cgi/doi/10.1073/pnas.2001049117 PNAS | April 7, 2020 | vol. 117 | no. 14 | 7573–7574 Downloaded by guest on October 1, 2021 5 M. D. Skinner, P. Lahmek, H. Pham, H. J. Aubin, Disulfiram efficacy in the treatment of alcohol dependence: A meta-analysis. PLoS One 9, e87366 (2014). 6 R. K. Fuller, E. Gordis, Does disulfiram have a role in alcoholism treatment today? Addiction 99,21–24 (2004). 7 J. Chick, Disulfiram: Cautions on liver function; how to supervise. Addiction 99, 25, author reply 27–28 (2004). 8 J. Chick, Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Saf. 20, 427–435 (1999). 9 M. Y. Balakirev, G. Zimmer, Mitochondrial injury by disulfiram: Two different mechanisms of the mitochondrial permeability transition. Chem. Biol. Interact. 138, 299–311 (2001). 10 E. Ekinci, S. Rohondia, R. Khan, Q. P. Dou, Repurposing disulfiram as an anti-cancer agent: Updated review on literature and patents. Recent Patents Anticancer Drug Discov. 14, 113–132 (2019). 11 K. Poelstra, J. Prakash, L. Beljaars, Drug targeting to the diseased liver. J. Control. Release 161, 188–197 (2012).

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